Regulated exocytosis is a key biological process in secretory cells, and has been extensively studied in neurons, which release neurotransmitters from their synaptic vesicles (1, 2). Many non-neuronal cells such as endocrine and exocrine cells contain secretory vesicles identified as dense-core vesicles, the contents of which exert a variety of biological effects (3). Secretory vesicle exocytosis occurs in the secretion of hormones in amine/peptide containing endocrine cells (4, 5), and in the secretion of digestive enzymes in exocrine cells (6).
Rab3, a subfamily of the small GTP-binding protein Rab family (7), plays an important role in the process of targeting, docking, priming and fusion in exocytosis (8). There are four isoforms (A–D) in the Rab3 family, all of which have been associated with regulated exocytosis (9–12). Several potential effectors of Rab3 have been identified, including rabphilin3 (13) and Rims (Rim1 and Rim2) (14, 15), and Noc2 (16). Rim1 and rabphilin3 expressed predominantly in the brain (13, 14), suggesting their involvement in synaptic vesicle exocytosis. While it is suggested, through studies of Rim1-deficient (Rim1−/−) mice and Caenorhabditis elegans, that Rim1 is involved in priming of synaptic vesicles (17–19), the role of rabphilin3 in synaptic vesicle exocytosis is not clear (20, 21).
Both Rim2 (15) and Noc2 (16) are expressed predominantly in neuroendocrine and endocrine cells (16), suggesting their involvement in secretory granules exocytosis (3). We have previously shown that Rim2, interacting with cAMP-GEFII (Epac2) and Piccolo, is responsible for cAMP-dependent, protein kinase A (PKA)-independent exocytosis of insulin granules (15, 22, 23).
The physiological function of Noc2 in exocytosis, however, remains unclear. By overexpressing Noc2 in PC12 cells, we and another group separately have found that Noc2 has positive (16) and negative (24) effects on Ca2+-triggered exocytosis.